Bile Acid Derivatives as FXR/TGR5 Agonists and Methods of Use Thereof

Abstract

The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combination thereof,The invention also provides pharmaceutical compositions comprising these compounds and methods of using this compounds for treating FXR-mediated or TGR5-mediated diseases or conditions.

1 - 17 . (canceled) 
     
     
         18 . A compound represented by Formula (III-10) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of:
 1) Halogen; 
 2) Hydroxyl; 
 3) Substituted or unsubstituted —C 1 -C 8  alkyl; 
 4) Substituted or unsubstituted —C 2 -C 8  alkenyl; 
 5) Substituted or unsubstituted —C 2 -C 8  alkynyl; 
 6) Substituted or unsubstituted —C 3 -C 8  cycloalkyl; 
 7) Substituted or unsubstituted aryl; 
 8) Substituted or unsubstituted arylalkyl; 
 9) Substituted or unsubstituted heterocycloalkyl; 
 10) Substituted or unsubstituted heteroaryl; 
 11) Substituted or unsubstituted heteroarylalkyl; and 
 12) —NR 10 R 11 ; 
 
 
         R 2  is hydrogen; 
         R c  is hydrogen; 
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         m is 0; 
         R 7  is ethyl; and 
         R 10  and R 11  are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8  alkyl, substituted or unsubstituted —C 2 -C 8  alkenyl, substituted or unsubstituted —C 2 -C 8  alkynyl, substituted or unsubstituted —C 3 -C 8  cycloalkyl, or R 10  and R 11  are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring. 
       
     
     
         19 . The compound of  claim 18 , wherein R 1  is amino, alkylamino, dialkylamino, halogen, C 1 -C 4 -alkyl; halogenated C 1 -C 4 -alkyl; C 1 -C 4 -alkenyl; phenyl-C 1 -C 4 -alkyl; substituted or unsubstituted C 3 -C 6 -cycloalkyl; C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl; C 3 -C 6 -heterocycloalkyl; C 3 -C 6 -heterocycloalkyl-C 1 -C 4 -alkyl; heteroaryl, substituted or unsubstituted aryl. 
     
     
         20 . The compound of  claim 18 , wherein R 1  is selected from the group consisting of fluoro, amino, methyl, ethyl, isopropyl, butyl, t-butyl, propyl, benzyl, allyl, vinyl, CF 3 , cyclohexyl, cyclopentyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising the compound of  claim 18  and a pharmaceutically acceptable carrier or excipient. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The pharmaceutical composition of  claim 21 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         29 . A method of treating nonalcoholic fatty liver disease or nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of  claim 18 . 
     
     
         30 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 29 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method of  claim 29 , wherein the compound is